tbuckley/cabot-search huggingface dataset:
PB2263: SUPPORTIVE CARE IN LOW-RISK MYELODYSPLASTIC SYNDROMES: ROLE OF ERYTHROPOIESIS STIMULATING AGENTS (ESAS)
Authors: C. Cerchione, G. Musuraca, B. Giannini, D. Nappi, F. Alfinito, G. Martinelli
Journal: HemaSphere (2022)

Background: Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. It’s matter of debate whether the clinical response is a result of proliferation and maturation of the dysplastic clone or stimulation of residual normal erythropoiesis by ESAs. Aims: Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS: an analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non trasfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed. Methods: 183 patients, treated with standard-dose ESAs, have been retrospectively analyzed. Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dl, mean serum EPO concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1-118). Results: ORR was 83.6% (153/183), no difference among WHO and IPSS subgroups was found: 132/183 (72.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease (non-responders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocytic-responders group 83.2% exhibits again macrocytosis after 3 months, while 16.8% become normocytic. In the normocytic-responders group 89.8% exhibits again normocytosis, while 10.2% become macrocytic: in these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic non-responders group 89% exhibit again macrocytosis after 3 months, while 11% become normocytic; in the normocytic group 76% exhibits again macrocytosis, while 24% become normocytic. Image:Summary/Conclusion: These preliminary data can suggest that, in the majority of MDS patients responsive to ESAs, the increase of Hb concentration occurs mainly stimulating erythroid production in MDS clones; in the minority of patients probably it happens recruiting residual polyclonal erythropoiesis. It is interesting to note that stimulating effects of ESAs last even when the expression of dysplasia progresses.
<i>Salmonella enterica</i> subsp. II serovar 4,5,12:a:- may cause gastroenteritis infections in humans
Authors: Meiying Yan, Yongming Zhou, Yang Cao, Zhenpeng Li, Xin Lu, Bo Pang, Shukun Wang, Biao Kan
Journal: Gut Microbes (2022)

Some serovars of Salmonella are not or rare found to cause salmonellosis in human. In our clinic-based surveillance, three rare Salmonella 4,5,12:a:- strains were recovered from three patients with diarrhea. To explore their genetic and epidemiological characteristics and pathogenesis, we conducted whole-genome sequencing, in vitro invasion assays in mammalian cells, and in vivo virulence assays in an animal model. The three isolates had indistinguishable molecular patterns and similar genome sequences, and clustered together with an isolate from edible fish traded among countries. The isolates had biochemical reactions identical with those of Salmonella subspecies enterica but belonged to subspecies salamae according to genome phylogeny, revealing a new serovar, S. enterica subsp. II serovar 4,5,12:a:-. The strains contained multiple virulence genes, elicited temporary bacteremia and enteritidis and caused cell damage in the mouse liver and cecum. This study provides evidence that this new Salmonella salamae serovar can infect humans and cause clusters of cases, and whole-genome sequencing detection and surveillance of Salmonella can help to accurately define Salmonella classification and clonality, improve diagnosis, facilitate outbreak detection and aid in the source tracing of salmonellosis epidemics.
P809: MODULATION OF ARACHIDONIC ACID PATHWAY BY IBUPROFEN RESULTS IN COMPLETE HEMATOLOGICAL RESPONSE IN GHOSAL HEMATODIAPHYSEAL DYSPLASIA WITHOUT NEED FOR CORTICOSTEROID
Authors: N. Barrett, C. McDonnell, M. Cotter
Journal: HemaSphere (2022)

Background: Ghosal hematodiaphyseal dysplasia (GHDD) is a rare autosomal recessive disorder characterized by pancytopenia and increased bone density of the long bones. First described in families of Indian and Middle Eastern descent, subsequent studies identified the genetic lesion in this disease as due to loss of function mutations in the TBXAS1 gene encoding thromboxane synthase, a key component of the arachidonic acid pathway responsible for the formation of thromboxane A2 from prostaglandin H2. As well as pancytopenia, laboratory features include platelet aggregation defects and increase in osteoblastic activity, the latter being the basis of increased bone density in patients with Ghosal syndrome. Simultaneously, loss of thromboxane synthase activity may be associated with shunting of prostaglandin precursors away from production of thromboxane into production of pro-inflammatory prostaglandins. This may be the mechanism responsible for the observed marrow suppression seen in these patients. We describe a 3 year old female of non-consanguineous parents of Filipino origin who presented with marked pancytopenia. Next Generation Sequencing bone marrow failure gene panel revealed a novel homozygous mutation in TBXAS1. Subsequent DXA scanning revealed increased bone mineral density consistent with the diagnosis (Z -score +2.4 for lumbar spine (L1-4)) although clinical sequelae of bony disease were not apparent. Aims: While multiple case reports document that these patients have hematological response to long term corticosteroid therapy, we hypothesized that inhibition of cyclooxygenase (COX) upstream of thromboxane synthase in the arachidonic acid pathway may be effective in this condition. Methods: Patient was treated with ibuprofen at regular therapeutic doses (approximately 30 mg/kg/24 hours daily initially) and serial full blood counts were monitored. Results: The patient exhibited a rapid and complete response to ibuprofen with normalization of full blood counts. The dose of ibuprofen was reduced to 10 mg/kg/day, and hematologic response is maintained on low dose after one year.The treatment is well tolerated with no side effects. Image:Summary/Conclusion: Treatment of GHDD with ibuprofen is a novel approach that offers clear potential benefits in comparison to the known adverse effects profile of long term corticosteroids. Bone density scan and markers are in process to ascertain the impact of this treatment on bone density, although this may take longer to show beneficial effects. The treatment was easily tolerated and well managed by the patient and family at home with minimum disruption to her quality of life.
P1691: COMPARISON OF IMPROVE, MODIFIED IMPROVE, IMPROVEDD AND PADUA RISK SCORES FOR VENOUS THROMBOEMBOLISM PREDICTION IN HOSPITALIZED COVID-19 PATIENTS
Authors: M. Lucijanic, I. Jurin, M. Sedinic, E. Soric, A. Sabljic, I. Hadzibegovic, T. Lucijanic, R. Kusec
Journal: HemaSphere (2022)

Background: Venous thromboembolism (VTE) imposes a significant burden of morbidity on COVID-19 patients. It is very challenging to predict and prevent these events from occurring due to high thrombogenicity of the disease and overlapping clinical presentations, despite of regular use of pharmacologic thromboprophylaxis. Aims: To evaluate predictive properties of several VTE prediction scores developed prior to COVID-19 era in a large cohort of hospitalized COVID-19 patients. Methods: We retrospectively evaluated all consecutive COVID-19 patients hospitalized in University Hospital Dubrava, Zagreb, Croatia in the period from 3/2020-6/2021. Data used were recorded as a part of the hospital Registry project (ClinicalTrials.gov Identifier: NCT05151094). VTE (deep venous thromboses (DVT) and pulmonary embolism (PE)) were considered if documented by objective imaging methods. We considered IMPROVE, modified IMPROVE, IMPROVEDD and Padua VTE risk scores. Scores were indirectly compared based on their AUC values obtained through ROC curve analysis. Cut-offs with highest Youden index were shown. Results: A total of 5959 patients were analyzed. Median age was 72 years and median Charlson comorbidity index was 4 points. There were 56.2% males, majority of patients had either severe (70.5%) or critical (15.3%) severity of COVID-19 symptoms at the time of hospital admission. There were 365 (6.1%) VTE, among them 137 (2.3%) DVT and 262 (4.4%) PE. Regarding VTE, all investigated scores demonstrated modest predictive properties with highest AUC observed for IMPROVEDD score (AUC 0.623, >3 points sensitivity 69% and specificity 49%) followed by modified IMPROVE (AUC 0.590, >1 point sensitivity 87% and specificity 29%), Padua (AUC 0.589, >4 points sensitivity 87% and specificity 29%) and IMPROVE (AUC 0.584, >1 point sensitivity 74% and specificity 43%) as shown in Figure. IMPROVEDD had significantly higher AUC in comparison to all other scores, whereas other scores had comparable AUC values. All scores could significantly discriminate patients with and without VTE. Overall higher AUC values were achieved for DVT than for PE prediction, with IMPROVEDD score having highest AUC values for both DVT and PE prediction (DVT AUC 0.650, >3 points sensitivity 75% and specificity 48%; PE AUC 0.603, >2 points sensitivity 88% and specificity 29%). Image:Summary/Conclusion: Predicting VTE in hospitalized COVID-19 patients cannot be relied on pre-COVID era developed VTE risk scores. D-dimer based score (IMPROVEDD) had best diagnostic properties in comparison to other scores.
PB1753: SYNERGISTIC ANTITUMOR EFFECT OF CHIDAMIDE WITH VENETOCLAX IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA BY SUPPRESSING PI3K/AKT SIGNALING
Authors: D. Song, C. Song, Z. Ge
Journal: HemaSphere (2022)

Background: Chidamide, an oral histone deacetylase (HDAC) inhibitor of the benzamide class that selectively inhibits HDAC1, 2, 3, and 10, is currently used for patients with peripheral T-cell lymphoma. ABT-199 (Venetoclax), BH3-mimetic, is a highly specific inhibitor of the anti-apoptotic protein Bcl-2. HDAC inhibitors have been shown to synergize effects with ABT-199 in acute myeloid leukemia (AML), cutaneous T-cell lymphoma (CTCL), and mantle cell lymphoma (MCL). Notably, T-ALL patients treated with ABT-199-based combination regimens showed promising efficacy. However, there are no reports about the combination of HDAC inhibitor with ABT-199 in T-ALL. Aims: This study is to examine the synergistic antitumor effect of chidamide in combination with ABT-199 in T-ALL cells. Methods: CCK-8 assays were employed to evaluate the synergistic effects of chidamide and ABT-199 on cell proliferation arrest in CEM and Molt4 T-ALL cells treated with vehicle control, chidamide, ABT-199, and chidamide+ABT-199 for 48 hours. Apoptosis was measured by cell staining with Annexin V+ propidium iodide (PI) following flow cytometry analysis. The distribution of the cell cycle was detected by flow cytometry with a PI staining assay. The gene expression upon the drug treatment is evaluated by qPCR and western blot. Results: Both chidamide and ABT-199 significantly inhibited the cell proliferation of CEM and Molt4 cells in a dose-dependent manner. The combination of chidamide with ABT-199 significantly increases the rate of cell proliferation arrest (Fig. 1A), and apoptosis (Fig. 1B) compared to the single drug control in both cell lines. Also, the chidamide alone or combined treatment significantly induced the G0/G1 phase arrest in the cells (Fig. 1C). Moreover, the Combination of chidamide with ABT-199 induced the up-regulation of apoptotic proteins, Bax and cleaved caspase-3, and down-regulation of anti-apoptotic protein, Mcl-1 compared to that of either single drug control (Fig. 1D). Similarly, chidamide alone or combined treatment induced the up-regulation of cell cycle regulatory protein, p21 in the cells (Fig. 1E). We also analyzed the pathway enrichment based on network pharmacology from T-ALL treated with chidamide and ABT -199 and found the PI3K/AKT is significantly enriched upon the drug treatment (Fig. 1F). Western blot results also showed that the combination treatment significantly down-regulated expression of PI3K and AKT, also the AKT phosphorylation (Fig. 1G). Image:Summary/Conclusion: The combination of chidamide with ABT-199 exerted a synergetic effect on cell proliferation arrest by suppressing PI3K/AKT signaling pathway. Our data also highlight the combination therapy in clinical application in T-ALL.
PB2292: AMSAN VARIANT OF GUILLAIN BARRE SYNDROME COMPLICATING THE RECOVERY PHASE OF COVID-19 RELATED DISEASE
Authors: A. M. Haidary, S. Noor
Journal: HemaSphere (2022)

Background: The novel coronavirus, since its first identification in China, in December 2019, has shown remarkable heterogeneity in its clinical behavior. It has affected humans on every continent. Clinically, it has affected every organ system. The outcome has also been variable, with most of the older patients showing grave outcomes as compared with the younger individuals. Here we present a rare and severe variant of Guillain-Barre syndrome that complicated the disease in recovery phase. Aims: To inform about a rare and life-threathening complication of COVID19 that can be treated with timely institution of IVIG/ Plasmapheresis Methods: Case reporting Results: A 60-year-old Afghan man, who had been recovering from symptoms related to novel coronavirus associated disease, presented with sudden onset of progressive muscle weakness and oxygen desaturation. Electrophysiological workup confirmed the diagnosis of Guillain-Barre syndrome, and early institution of intravenous immunoglobulin resulted in complete resolution. Summary/Conclusion: In our case report, we presented the rare and most severe variant of GBS, AMSAN, that complicated COVID-19-related disease in its recovery phase. To our knowledge, this was the first case of AMSAN complicating COVID-19. Clinical suspicion and prompt diagnosis led to early intervention, leading to complete recovery. While the world is entering the second wave of COVID-19, clinicians, particularly who manage old-age individuals, need to have insight into this dreadful but manageable complication of COVID-19-related disease.
Impact of autologous hematopoietic cell transplantation on disease burden quantified by next‐generation sequencing in multiple myeloma treated with quadruplet therapy
Authors: Susan Bal, Binod Dhakal, Rebecca W. Silbermann, Timothy M. Schmidt, Bhagirathbhai Dholaria, Smith Giri, Saurabh Chhabra, Eva Medvedova, Kelly N. Godby, Anita D'Souza, Aric C. Hall, Pamela Hardwick, Jim Omel, Robert F. Cornell, Parameswaran Hari, Natalie S. Callander, Luciano J. Costa
Journal: American Journal of Hematology (2022)

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.
PB2336: BURDEN OF HOSPITALIZATION, COSTS AND CO-MORBIDITIES IN MEDICAID PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): ANALYSIS OF NATIONAL IN-PATIENT HOSPITAL DATABASE
Authors: S. Aggarwal, S. Kumar, H. Topaloglu, A. Bela, O. Topaloglu
Journal: HemaSphere (2022)

Background: Acute lymphocytic leukemia (ALL) is a type of cancer of the blood and bone marrow. ALL is the most common type of cancer in children. Aims: To analyze trends in hospital length of stay, total costs and co-morbidities in Medicaid patients with Acute Lymphoblastic Leukemia (ALL). Methods: The National Inpatient Sample (NIS) data set from the Healthcare Cost and Utilization Project was utilized in order to determine the number of hospital admissions for Acute Lymphoblastic Leukemia. Thirty co-morbidities were assessed using Elixhauser scoring. The outcomes assessed include length of stay (LOS), total charges, co-morbidity score, mortality rate and emergency room visits. Results: There were an estimated 18,575 hospitalizations with a diagnosis of ALL that were covered by Medicaid. The mean age was 17.35 (SD 15.59) years and 42% of the patients were female. The mean hospital length of stay for Medicaid patients with ALL was 8.8 (SD 13.17) days (Median was 4 days). The mean hospital charges were $122,626 (SD $259,709). The mean comorbidity score was 1.31 (SD 1.44). The in-hospital mortality rate was 1.75%. The vast majority of the patients were Hispanic (45%), followed by White (34%), Black (11%) and Asian (3%). The top five listed co-morbid conditions were were Fluid and Electrolyte Disorders (24%), Coagulopathy (18%), Hypertension (12%, Depression (9%) and Weight Loss (8%). The top 3 procedure codes were for Blood Transfusion, Infusion Device into Superior Vena Cava and Bone Marrow Extraction. Approximately, 72% of Medicaid patients were admitted to the hospital via the emergency room visit. Summary/Conclusion: Acute Lymphoblastic Leukemia (ALL) covered by Medicaid pose significant hospital burden. There is a need for new treatment options for ALL patients.
2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19
Authors: Biykem Bozkurt, Sandeep R. Das, Daniel Addison, Aakriti Gupta, Hani Jneid, Sadiya S. Khan, George Augustine Koromia, Prathit A. Kulkarni, Kathleen LaPoint, Eldrin F. Lewis, Erin D. Michos, Pamela N. Peterson, Mohit K. Turagam, Tracy Y. Wang, Clyde W. Yancy
Journal: Journal of the American College of Cardiology (2022)
Abstract LB130: High-throughput RNA sequencing directly from cell lysates enables reproducible phenotypic profiling for assessing novel compounds and treatments in cancer research
Authors: Andrea O'Hara, Michael Stephens, Ilaria DeVito, Laure Turner, Christopher Mozdzierz, Haythem Latif, Ginger Zhou
Journal: Cancer Research (2022)

Abstract New oncology therapies are driven by multiple approaches, with a heavy emphasis on small-molecule therapeutics to target cancer cells and provide a therapeutic benefit to cancer patients. These small-molecule compounds can be used as a stand-alone treatment approach or may be combined with other compounds to bring enhanced effects. Compound therapeutic discovery relies heavily on high-throughput screening assays for measurement of phenotypic responses following compound treatment of oncology cell cultures which can range from very targeted assays to wide-ranging unbiased approaches. Standard whole transcriptome RNA-seq is a preferred method for unbiased measurement of phenotypic responses but is often overlooked due to limited scalability and high sample screening costs. To address these challenges, we have developed a high-throughput gene expression (HT-GEx) assay that combines a variety of strategies to enable a low-cost and high-throughput alternative to standard RNA-seq. First, a simplified workflow removes upstream RNA isolation steps and tags transcripts directly from cell lysate. This is achieved by incorporating both a sample barcode and a unique molecular index (UMI) during the reverse transcription reaction. Next, we leverage a 3’ end counting approach to enable a reduction in sequencing depth coverage (i.e. sample cost) without compromising gene detection sensitivity. With these key advances, a high-plex and high-throughput screening assay is achievable at a reduced cost by removing the need to purify RNA, tagging transcripts early in the workflow to allow pooling of samples and reducing sequencing depth. We have combined these high-throughput and cost-saving strategies and present results which confirm HT-GEx offers results on par with standard RNA-seq. Gene detection sensitivity based on number of genes detected per millions of reads is highly similar, with gene detection sensitivity saturated at approximately 2 million reads. Additionally, the number of genes detected between replicates for RNA samples and lysate samples demonstrate strong linear correlation, implying highly reproducible results. Thus, high-throughput gene expression is an ideal method for phenotypic screening in oncology cell lines following stand-alone or combined compound treatments. Citation Format: Andrea O'Hara, Michael Stephens, Ilaria DeVito, Laure Turner, Christopher Mozdzierz, Haythem Latif, Ginger Zhou. High-throughput RNA sequencing directly from cell lysates enables reproducible phenotypic profiling for assessing novel compounds and treatments in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB130.